Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib
Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib
Abstract Palbociclib is a CDK4/6 inhibitor approved for metastatic estrogen receptor positive breast cancer. In addition to G1 cell cycle arrest, palbociclib treatment results in cell senescence, a phenotype that are not readily explained by CDK4/6 inhibition. In order to identify a molecular mechanism responsible for palbociclib-induced senescence, we performed thermal proteome profiling of MCF7 breast cancer cells. In addition to affecting known CDK4/6 targets, palbociclib induces a thermal stabilization of the 20S proteasome, despite not directly binding to it. We further show that palbociclib treatment increases proteasome activity independently of the ubiquitin pathway. This leads to cellular senescence which can be counteracted by proteasome inhibitors. Palbociclib-induced proteasome activation and senescence is mediated by reduced proteasomal association of ECM29. Loss of ECM29 activates the proteasome, blocks cell proliferation and induces senescence. Finally, we find that ECM29 mRNA levels are predictive of relapse-free survival in breast cancer patients treated with endocrine therapy. In conclusion, thermal proteome profiling identifies the proteasome and ECM29 protein as mediators of palbociclib activity in breast cancer cells.
Bj?rklund Mikael、Peltier Julien、Gierli¨?ski Marek、Trost Matthias、Miettinen Teemu P.、H?rtlova Anetta、Jansen Valerie M.
Division of Cell and Developmental Biology, University of DundeeMRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee||Institute for Cell and Molecular Biosciences, Newcastle UniversityDivision of Computational Biology, University of DundeeMRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee||Institute for Cell and Molecular Biosciences, Newcastle UniversityDivision of Cell and Developmental Biology, University of Dundee||MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee||MRC Laboratory for Molecular Cell Biology, University College London||Koch Institute for Integrative Cancer Research, Massachusetts Institute of TechnologyMRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee||Institute for Cell and Molecular Biosciences, Newcastle UniversityDivision of Hematology-Oncology, Vanderbilt University Medical Center||Eli Lilly and Company
肿瘤学基础医学分子生物学
cellular thermal shift assaythermal proteome profilingpalbociclibCDK4CDK6proteasomeubiquitinECM29breast cancersenescence
Bj?rklund Mikael,Peltier Julien,Gierli¨?ski Marek,Trost Matthias,Miettinen Teemu P.,H?rtlova Anetta,Jansen Valerie M..Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/202770.点此复制
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